Our long-term goal is to investigate the pathophysiology of pancreatitis and seek to develop potential clinical interventions and preventative measures. This study aims to investigate the initiating mechanisms of acute pancreatitis. Previous research by Dr. Wei-Chun Chin has demonstrated that ion-exchange processes play a critical role in mucus secretion (Nature, 1998). Raraty et al (2000) proposed a similar exchange could trigger the premature digestive enzyme activation in the pancreas leading to acute pancreatitis. However, this approach has never been thoroughly examined. In this study, we plan to test the hypothesis that an ion-exchange process involving calcium and potassium could lead to premature activation of digestive enzymes in pancreatic cells and acute pancreatitis. Experimental training will include demonstration of nicotine and ethanol as factors which can induce [Ca2+]c increase in pancreatic acinar cells. In addition, we plan to demonstrate that Ca2+ can be released from zymogen granules (ZGs) under nicotine and alcohol stimulation. We will determine the contribution of extracellular and intracellular Ca2+ pools to the nicotine-induced and ethanol induced [Ca2+]c increase. [unreadable] [unreadable]